tbuckley/cabot-search huggingface dataset:
Examining clinical trial eligibility for oncology patients with human immunodeficiency virus (HIV): A global cross-sectional analysis.
Authors: Umar Abdullahi, Sammy Shaya, Habana Dinizulu, Emily Sampey, David Appleton, Matthew Concannon, Donna M. Graham
Journal: Journal of Clinical Oncology (2023)

6554 Background: People Living with HIV (PLWH) are at higher risk of developing cancer, and malignancy is the most common cause of death in PLWH in the USA . In 2017 a joint research statement by the American Society of Clinical Oncology and Friends of Cancer Research (ASCO-FCR) examined trial inclusivity, stating PLWH should not be excluded from clinical trials due to HIV positivity alone without justification. It also provided guidance for designing trial inclusion criteria using CD4 count, use of antiretroviral therapy (ART), ART-related drug interactions and HIV-associated complications. To review incorporation of ASCO-FCR recommended wording and current compliance, we examined global eligibility for PLWH in clinical trials. Methods: Clinicaltrials.gov was searched on 15 Nov 2022 for open and recruiting trials worldwide, using terms ‘advanced cancer’ and ‘interventional’. Trials lacking systemic treatment were deemed non-evaluable. Evaluable studies’ eligibility criteria were manually reviewed for specific criterion excluding PLWH or diagnosis/history of immunodeficiency (outright exclusion). Therapy type and study phase were captured and their relationships to outright exclusion were significance tested using odds ratios (OR) with 95% confidence intervals (CI). Results: The search rendered 2388 evaluable clinical trials. Eligibility criteria outrightly excluded PLWH in 1194 (50%) , of which 1113 (93%) were early phase trials (Phase 0-2). 206 evaluable trials (8.6%) permitted inclusion of PLWH aligned with ASCO-FCR guidance, including 3 (0.1%) with a cohort for PLWH. AIDS-defining illness was an exclusion criterion in 27 trials (1%), and specific interactions to ART in 10 (0.4%). Early phase trials had a significantly higher likelihood of outright exclusion of PLWH when compared with late phase trials (OR 2.98; 95% CI 2.16-4.11, p&lt;0.0001). Trials investigating immunomodulatory agents were more likely to outrightly exclude PLWH than those investigating other drug classes (OR 1.60; 95% CI 1.36-1.88, p&lt;0.0001). Criteria which may implicitly exclude PLWH were identified, including 204 (8.5%) citing active/chronic/severe infection, 189 (7.9%) listing CYP and P-gp interaction criteria and 3 (0.1%) "immunodeficiency". Conclusions: Despite adequate time to incorporate, most currently recruiting oncology clinical trials do not use ASCO-FCR guidance for including PLWH. Half of evaluated trials excluded PLWH without reason. Early phase and immunotherapy trials were significantly more likely to exclude PLWH without exception, despite data to support immunotherapy use for PLWH. Covert inclusionary barriers exist in criteria that lack HIV-specific guidance, and this may further exclude PLWH. Consideration of recommendations and guidance in eligibility criteria for oncology trials is critical to address current inequities in care for PLWH and cancer.
Readability and understandability of instruments for collecting patient-generated data (PGD).
Authors: Camila Kelly Chiodi, Johanna Arvis, Elise Martin, Aude Barbier, Antonio Di Meglio, Guillemette Jacob, Gwenn Menvielle, Sibille Everhard, Francis Guillemin, Ines Maria Vaz Duarte Luis, Maria Alice B Franzoi
Journal: Journal of Clinical Oncology (2023)

e18534 Background: PGD are crucial to inform and optimize cancer care. These may include patient-reported outcomes measures (PROMs), patient-reported experience measures (PREMS), or patient preferences information (PPI). The increasing use of PGD has led to the need for the adaptation of instruments to different languages and cultures. Recent data has brought attention to the additional need to consider patients’ ability to understand written information included in PROMs. Low health literacy is associated with higher risk for quality-of-life deterioration and generates disparities, including underrepresentation in cancer research. Aiming at improving equity and representation, we evaluated readability and understandability of nine French-language PROMs that are currently used in a contemporary cohort of breast cancer survivors. Methods: Readability of PROMs was assessed using the Flesh Reading Ease Score (FRES), the Gunning’s Fog Index (FOG), and the FRY graphics (yielding a mean score representing the n. of school years required to understand the respective text). Readability was considered ideal if mean score ≤6 th grade level and acceptable if between 6-8 th grade. Understandability was evaluated using the Patient Education Materials Assessment Tool (PEMAT, range 0-100%, higher scores corresponding to easier understandability) and defined as ideal if PEMAT ≥ 80%. Plain-language best practice was met if both readability and understandability were ideal. The Evaluative Linguistic Framework for Questionnaires (ELF-Q) provided additional qualitative elements to assess understandability. Two native French speakers, including a patient representative, independently evaluated each PROM. An additional independent assessment was requested if discordance. Results: None of the 9 PROMs evaluated had ideal readability scores, and only 1 had an acceptable score. Understandability ranged from 55-91%, and only 3 PROMs had ideal scores. None of the instruments met the definition of plain-language best practice. ELF-Q identified points for improvement in several dimensions of the PROMs (Table). Conclusions: The use of comprehensive linguistic and cultural frameworks during the development and translation of self-reported PGD instruments may improve experience and engagement of patients with lower literacy and foster equity and representation in cancer cohort studies. [Table: see text]
Tertiary lymphoid structure prevalence and prognostic value in cervical cancer.
Authors: Grace Gorecki, Lan Gardner Coffman, Sarah E. Taylor, Tullia C. Bruno
Journal: Journal of Clinical Oncology (2023)

e17521 Background: Recurrent or progressive cervical cancer have limited second-line treatment options. Response rates are often poor to second-line therapy (average response rate of 15%). Identification of factors which predict response to immunotherapy and targets to enhance the immune response are critically needed in cervical cancer. Chronic inflammation can initiate an immune response in non-secondary lymphoid organs (SLO) and form a Tertiary Lymphoid Structure (TLS). TLS is composed of immune cells clustered and organized and responsible for immune cell chemotaxis, which impacts cancer therapeutic response. Chemokine ligand 13 (CXCL13) is related to B cell attraction and TLS formation. Recent work from our group demonstrated human papilloma virus (HPV) positive head and neck squamous cell carcinoma (HNSCC) exhibited greater tumor infiltrating B cells (TIL-Bs) and TLS vs HPV negative disease indicating a role for viral infection in immune infiltration. Most cervical cancer is caused by HPV infection, therefore we investigated prognostic significance of immune infiltration in cervix cancer. Methods: A cohort analysis was conducted on 43 patients diagnosed with early stage cervical cancer. The presence of B cells, CD8 T cells, and CXCL13 was analyzed using singleplex immunohistochemistry staining. We separated infiltration into high infiltration and low infiltration, defined by their median value. TLS was identified using a multiplex immunofluorescence for TLS maturity panel. Histological findings were associated with cohort data. Results: High intratumoral infiltration of CD8 T cells was associated with longer overall survival in cancer patients. Median survival was 45 months for low infiltration group, whereas it was not reached by higher T cell infiltration (p &lt; 0.05). The prognostic value of T cell infiltration was stronger in adenocarcinoma, typically associated with worse outcomes, than in squamous cell carcinoma. In adenocarcinoma, median survival was 58 months for low T cell infiltration, it was not reached by high infiltration group. CXCL13 levels were prognostic for recurrence-free survival, with median survival of 53 months in low expression group and not reached in high CXCL13 presence group (p &lt; 0.05). The presence of TLS compared to low B cell infiltration was associated to higher survival, with 0% of deaths in the TLS group vs 40% in low B cell infiltration. While there was no correlation between TIL-B and patient outcomes, the presence of B cells in the aggregation process and higher CXCL13 levels were associated with improved survival, with 9% deaths vs 36% in low B cell group, possibly due to the support of TLS formation by B cell aggregation surrounded by CXCL13. Conclusions: Our study suggests that the presence of TLS, whether forming or established, is linked to improved clinical outcomes in cervical cancer. Further research is necessary to investigate the response of this cancer type to immunotherapy.
Clinicogenomic analysis of rare histologic variants of pancreatic carcinoma: Undifferentiated carcinomas with and without osteoclast-like giant cells.
Authors: Jamie Mills, Valerie Gunchick, Jiaqi Shi, Aaron M. Udager, Timothy Frankel, Vaibhav Sahai, Mark Zalupski
Journal: Journal of Clinical Oncology (2023)

e16001 Background: Undifferentiated carcinoma (UC) is a rare subtype of pancreatic carcinoma and can present with or without osteoclast-like giant cells (OGC). This 2010 delineation complicates interpretation of prior studies comparing UC to pancreatic ductal adenocarcinomas (PDAC). Limited retrospective data suggest UC-OGC tumors correspond to younger age, larger size, and worse prognosis compared to UC. The role of OGC is hypothesized to alter the immune microenvironment of tumors, leading to different response to therapy compared to PDAC. Methods: The aim of the study was to assess the clinical outcomes, histology (H&amp;E), targeted genomics panel, transcriptomics (RNA panel and CIBERSORT-X), and multiplex immunofluorescence (mIF) to assess the tumor immune milieu in a cohort of adult patients with UC or UC-OGC compared to PDAC. Results: We identified 32 patients with UC and 15 with UC-OGC treated at Michigan Medicine between 2005 and 2021. The demographics, presenting symptoms, tumor size, and CA 19-9 were similar between cohorts. In patients with advanced cancers, median survival was 2.6 months (N = 22) vs 8.13 months (N = 2) for UC and UC-OGC, respectively (p = 0.27). R0 resection was completed in 10 (31%) patients with UC compared to 13 (87%) with UC-OGC; median survival was 17.0 months vs 145.0 months, respectively (p = 0.03). Genomic landscape of UC and UC-OGC was similar to PDAC (TCGA; N = 159), with KRAS and TP53 mutations at similar rates. However, the transcriptome revealed significantly increased M2 macrophages and CD4 - 8 - (γδ) T-cells with significantly decreased regulatory T-cells (Tregs) in UC/UC-OGC (N = 10) compared to PDAC (p &lt; 0.05). These data were corroborated by mIF with significantly reduced Tregs (p &lt; 0.046) and trend toward increased M2 macrophages (p &lt; 0.055) in UC/UC-OGC (N = 17), but not CD8 + T cells, which were significantly enriched in PDAC (p &lt; 0.0001; N = 17). Conclusions: Overall, this study demonstrates significantly longer survival in patients with UC-OGC compared to UC in both advanced and resected patients. Increased pro-tumorigenic M2 macrophage infiltration and decreased Tregs in the tumor immune milieu of UC/UC-OGC suggests a potential role of macrophage inhibitors and other immune-modulatory therapies in combination with chemotherapy for these rare variants of pancreatic cancer.
Determinants of resistance to nivolumab (nivo) monotherapy investigated through genomic and transcriptomic analysis of renal cell carcinoma (RCC) tumors from the HCRN GU16-260 study.
Authors: David A. Braun, Kelly Street, Opeyemi Jegede, Neil Ruthen, Miya Hugaboom, Nicholas R Schindler, David F. McDermott, Elizabeth R. Plimack, Jeffrey A. Sosman, Naomi B. Haas, Michael E. Hurwitz, Hans J. Hammers, Sabina Signoretti, Michael B. Atkins, Catherine J. Wu
Journal: Journal of Clinical Oncology (2023)

4524 Background: Nivo monotherapy demonstrated anti-tumor activity in treatment-naïve RCC in Part A of HCRN GU16-260 across all IMDC groups and in multiple histologies. Patient tumor samples were collected to characterize the tumor-immune microenvironmental determinants of effective anti-tumor immunity with nivo. Methods: Whole exome sequencing (WES) was performed on formalin-fixed, paraffin-embedded tissue collected within one year prior to nivo. For single-cell RNA-sequencing (scRNA-seq), eligible patients (pts) with any RCC histology underwent tumor biopsy prior to and/or at resistance to nivo monotherapy. Gene expression signatures discovered through scRNA-seq were used to interrogate previously published bulk transcriptomic data of nivo in the treatment-refractory setting. Results: WES analysis (n = 96 tumors) identified recurrent focal amplifications within chromosome 11q13 (amp11q13), which was observed in 6 of 18 (33.3%) of tumors from pts with progressive disease (PD) compared to 0 of 20 (0%) of tumors from pts with complete or partial response (CR/PR; p = 0.005). amp11q13 was associated with worse progression free survival (PFS; p = 0.008) and overall survival (OS; p = 0.010). ScRNA-seq was performed on tumors from 17 pts (8 with baseline only, 7 with progression only, and 2 with paired baseline and progression samples) across 7 trial sites. Trajectory inference analysis of tumor-infiltrating T cells revealed a bifurcating structure, starting with naïve T cells and ending either in terminally exhausted CD8+ T cells or SLAMF7+ CD8+ T cells. Surprisingly, the SLAMF7+ T cell population expressed high levels of cytotoxic genes (including GZMA, GZMB, GNLY) and markers of tissue residency ( ZNF683/HOBIT and ITGAE/CD103). Of the 14 pts with at least 100 sequenced tumor-infiltrating T cells, the presence of a higher percentage of SLAMF7+ CD8+ T cells (relative to total T cells) was associated with primary resistance to nivo (mean percentage in PD [n = 4] pts 32.7%; stable disease [n = 4] pts, 9.1%; CR/PR [n = 6] pts, 2.2%; p = 0.019 for CR/PR vs PD). Of 172 pre-treatment tumors from the nivo arms of the CheckMate-009/010/025 trials that we analyzed by bulk RNA-seq, a signature score derived using genes expressed in the SLAMF7+ CD8+ T cell trajectory branch was enriched in pts with PD compared to CR/PR as best response (p = 0.032). Conclusions: Bulk genomic and single-cell transcriptomic analyses uncovered somatic alterations (amp11q13) and infiltrating T cell populations ( SLAMF7+ CD8+) associated with resistance to frontline nivo monotherapy in a phase II study in RCC. Additional independent and functional validation studies are in progress.
Development and validation of a non-invasive cfDNA targeted sequencing assay for early-stage hepatocellular carcinoma detection using cfDNA methylation and fragmentomics.
Authors: Rui Liu, De-Zhen Guo, Ao Huang, Cheng-Cheng Ma, Min-Jie Xu, Yi-Ying Liu, Ming-Yang Su, Hua Chen, Yun-Zhi Zhang, Qi-Ye He, Zhi-Xi Su, Xin-Rong Yang, Jia Fan, Jian Zhou
Journal: Journal of Clinical Oncology (2023)

4128 Background: Hepatocellular carcinoma (HCC) is one of the most common cancers in China, and one of the leading causes of cancer-related deaths in the country. With a 5-year survival rate of only 15-20%, early detection is crucial to improve the treatment and survival of HCC patients. Currently, alpha-fetoprotein (AFP) is commonly used as a serum marker for HCC, but it is not a sufficiently specific and can cause false positive readings due to elevated levels caused by other liver conditions. An alternative method is to use circulating free DNA (cfDNA) released by tumor cells as cancer-screening targets, which has been shown to be a more sensitive and specific biomarkers for HCC detection. This study aims to develop a non-invasive screening assay based on cfDNA features to improve the detection of early-stage HCC. Methods: Candidate methylation markers for HCC detection were collected and evaluated using GEO, TCGA and in-house datasets, 1601 of which were incorporated into a targeted sequencing panel named HcSeer. Multiple types of cfDNA features were constructed from the sequencing data, which included methylation-related features such as methylation haplotype blocks (MHBs) and methylated haplotype fraction (MHF), and fragmentomics features such as end motif and CNV. For model building, Cancer and healthy plasma samples were randomly divided into a training and a testing set at a 2:1 ratio. A two-step deep neural network model was built to classify HCC using selected features of both types. Results: We previously enrolled a total of 401 plasma samples (200 healthy, 201 HCC) for model construction and the performance of the HcSeer model have been documented. An independent validation cohort of 421 plasma samples (280 healthy, 141 HCC) was currently collected from different centers. In this independent validation, the HcSeer model achieved an AUC of 0.98 with a sensitivity of 96.5% at a specificity of 96.4%. Importantly, HcSeer maintained a high sensitivity for HCC across all stages: 94.3%, 96%, 100% and 100% for stage I – IV cases, respectively. When compared to AFP, HcSeer achieved a significantly higher sensitivity of 94% than AFP’s 55% in 137 HCC cases having AFP level tested. When AFP level was combined with the HcSeer model, the sensitivity for HCC further increased to 96%. Conclusions: This study demonstrated that the DNA methylation and fragmentomics patterns of cfDNA can accurately distinguish HCC and healthy plasma samples, particularly in the early stages of HCC. The combination of the HcSeer and AFP further improved the accuracy of the prediction. Although this study was limited in sample size, it clearly showed the potential of the HcSeer assay for accurate HCC detection in blood.
Phase II trial of mini-hyper-CVD-inotuzumab (InO) followed by blinatumomab (blina) consolidation in patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL).
Authors: Cedric Christophe Nasnas, Elias Jabbour, Fadi Haddad, Nicholas James Short, Walid Macaron, Marianne Zoghbi, Lewis Fady Nasr, Nitin Jain, Emmanuel Almanza, Koji Sasaki, Farhad Ravandi, Partow Kebriaei, Xuelin Huang, Guillermo Garcia-Manero, Tapan M. Kadia, Sa A Wang, Jovitta Jacob, Rebecca Garris, Susan M. O'Brien, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2023)

e19037 Background: Promising results were seen with low intensity chemotherapy mini-Hyper-CVD (mini-HCVD) in combination with InO in R/R ALL. Adding blina may further improve outcomes. Methods: Pts with R/R Philadelphia-negative B-ALL were treated with mini-HCVD (Cycles 1, 3, 5, 7) and methotrexate/cytarabine (Cycles 2, 4, 6, 8) for 8 cycles. Initially, InO was given on Day (D) 3 of the first 4 cycles at the dose of 1.8-1.3 mg/m 2 in Cycle (C) 1, followed by 1.3-1.0 mg/m 2 in subsequent cycles. POMP maintenance was for a total of 3 yrs. Protocol was amended after pt #67 to add 4 cycles of blina after 4 cycles of mini-HCVD+InO. InO was given on D2 and 8 at the dose of 0.6 and 0.3 mg/m 2 in C1, and then on D2 and 8 at the dose of 0.3 mg/m 2 in subsequent cycles; blina was given at standard dose in C5-8. Maintenance was reduced to 12 cycles of POMP with 1 cycle of blina after each 3 cycles of POMP for a total of 4 cycles. Rituximab was given for CD20+ disease. All pts received 8 doses of intrathecal chemotherapy. Results: Between 2/2013 and 7/2021, 110 pts were treated. Patient characteristics are shown in the table. 79 (72%) pts were treated in Salvage (S) 1, and 31 (28%) in S2+. 21 (19%) pts had received prior ASCT. 91 (83%) pts responded (complete remission, 63%). The overall response rate was 93% in S1, 59% in S2, and 57% in S3+. The rates of MRD negativity by flow were higher in S1 vs S2+ (89% vs 67%; P=0.047). 53 (48%) pts underwent ASCT. After a median follow-up of 48 months (mo) (range, 9-115), the median OS and RFS were 17 mo (4-yr, 36%) and 13 mo (4-yr, 37%), respectively. Pts in S1 had better OS compared with S2+ (4-yr OS, 43% vs 18%; P&lt;0.001). The 4-yr RFS was 38% in S1 and 27% in S2+ ( P=0.14). In S1, 41 pts were treated before the amendment and 38 after the amendment; their 4-yr OS was 41% and 48% ( P=0.99), and their 4-yr RFS was 39% and 36%, respectively ( P=0.95). A landmark analysis of pts who achieved remission showed no survival difference between pts who did or did not undergo ASCT, with 4-yr OS of 49% and 48% ( P=0.98), and 4-yr RFS of 46% and 37% ( P=0.68), respectively. Sinusoidal obstruction syndrome (SOS) was noted in 10 (9%) pts, and its incidence decreased from 13% with single dose of InO to 2% with lower and fractionated doses of InO ( P=0.056). Conclusions: The combination of mini-HCVD and reduced-dose InO with sequential blina improved the outcomes of pts with R/R ALL. The new treatment schedule resulted in a lower rate of SOS compared to the original schedule. Clinical trial information: NCT01371630 . [Table: see text]
A novel patient-centric longitudinal data registry platform to generate insights into real-world cholangiocarcinoma (CCA) clinical practice.
Authors: Amanda Nottke, Milind M. Javle, Mitesh J. Borad, Nilofer Saba Azad, Elise Brimble, Richard L Martin, Conner OBrien, Stacie Lindsey, Melinda Bachini, Shishir K. Maithel
Journal: Journal of Clinical Oncology (2023)

4084 Background: Treatment of advanced CCA has changed dramatically over the past five years with the advent of molecularly targeted therapy, now approved in the 2nd line and beyond. However, real world utilization of molecular profiling and targeted therapy is still unknown and these data are critical to empower treatment decision-making. Methods: In 2019, the Cholangiocarcinoma Foundation (CCF) and Ciitizen (a wholly owned subsidiary of Invitae Corporation) collaboratively launched a registry platform that directly consents patients and collects comprehensive medical records. De-identified data including clinical characteristics, molecular testing, interventions, and outcomes are extracted and standardized for research use. The data is longitudinal with regularly planned updates; registry participants can be re-engaged to obtain additional data and communicate tailored insights. Results: We quantified the rate of molecular testing, the presence of targetable biomarkers, and the utilization and outcomes on matched targeted therapies for 372 individuals with CCA. 328 (88.2%) individuals had molecular testing, with the identified targetable mutations and matched therapies reported. Of 328 individuals who had molecular testing, 111 (33.8%) individuals had one or more targetable mutations (116 mutations total). Only 46% (51) of individuals with targetable mutations received targeted therapy. Of the 54% (60) individuals with targetable mutations that did not receive any matched therapy, the majority (61.7%, 37) were in early disease or first line of treatment and therefore not yet eligible for targeted therapy. These individuals will be informed that based on their molecular profile, a targeted therapy may be an option, and suggest they discuss with their treating physician. Conclusions: A novel prospectively-maintained database registry for CCA has been formed in collaboration between a patient advocacy organization (CCF) and industry (Invitae). Prevalence of actionable biomarkers was higher than historically expected and may reflect patient utilization bias of the registry platform. Molecular profiling and access to targeted therapeutics remains suboptimal at this time in CCA. Future directions for the registry include identifying and targeting disparities in care and supporting biopharmaceutical development and regulatory decisions. [Table: see text]